Epilepsy afflicts around one percent of the world's population. Unfortunately approximately a third of all affected individuals do not have their seizures controlled by currently available drugs. Therefore there is a pressing need for new classes of therapeutic options, requiring an improved understanding of the mechanisms that regulate plasticity in the nervous system. Recent work from my lab suggests that perturbation of energy metabolism may represent a novel route to controlling neuronal plasticity (Garriga-Canut et al, 2006). This application will explore the mechanism by which metabolic perturbation controls aspects of neuronal plasticity - specifically, i) epigenetic regulation of activity- dependent genes and ii) metabolic regulation of signaling cascades that control Long Term Potentiation (LTP) in the mouse hippocampus. Our previously published work and more recent preliminary data suggests that two key sensors of energy metabolism -AMP activated Protein kinase (AMPK) and C-terminal Binding Protein (CtBP) act to regulate neuronal plasticity in an acute cytoplasmic and post-translational manner and also a chronic epigenetic manner respectively. The function of both AMPK and CtBP can be modulated with small molecule pharmaceuticals that are well tolerated in vivo and we propose that either might represent attractive novel therapeutic targets for the treatment of epilepsy. This proposal aims to address the broad question of how energy metabolism can control i) epigenetic regulation of gene transcription and ii) kinase regulation of neuronal signaling cascades to modulate neuronal plasticity in the hippocampus. The findings will facilitate the generation of therapies that work through controlling sensors of energy metabolism to control plasticity in conditions such as epilepsy. PUBLIC HEALTH RELEVANCE: Epilepsy afflicts around one percent of the world's population but unfortunately approximately a third of all affected individuals do not have their seizures controlled by currently available drugs. Therefore there is a pressing need for new classes of therapeutic options, requiring an improved understanding of the molecules and mechanisms that function in the nervous system. Recent work from my lab suggests that metabolism may represent a novel route to controlling epilepsy and this application will explore the mechanism by which 2 sensors of metabolism (CtBP and AMPK) control neuronal function or 'plasticity'. The mechanisms and drugs we study here will hopefully lead to therapies that result in 'no seizures and no side effects'for the millions of people around the world with epilepsy.